International Lung Cancer Consortium Research Articles

No genetic causal association between human papillomavirus and lung cancer risk: a bidirectional two-sample Mendelian randomization analysis

IntroductionSeveral observational or retrospective studies have previously been conducted to explore the possible association between lung cancer and human papillomavirus (HPV) infection. However, there may be inconsistencies in the data and conclusions due to differences in study design and HPV testing methods. There are currently no studies that provide conclusive evidence to support the involvement of HPV in the occurrence and development of lung cancer. Therefore, the relationship between HPV and lung cancer remains controversial and uncertain. This study aimed to explore whether HPV infection is causally related to lung cancer risk by systematically performing a two-way Two-Sample Mendelian Randomization (TSMR) analysis.MethodsIn the International Lung Cancer Consortium (ILCCO) genome-wide association study dataset, we included 11,348 lung cancer (LUCA) cases, including 3275 squamous cell carcinoma (LUSC) cases, 3442 adenocarcinoma (LUAD) cases, and 15,861 cases of control. Using genetic variants associated with the HPV E7 protein as instrumental variables, we summarized statistics associated with HPV infection in the MRC IEU OpenGWAS database, which included the HPV-16 E7 protein and the HPV-18 E7 protein. Two-sample Mendelian randomization (MR) results are expressed as odds ratios (OR) and 95% confidence intervals (CI).ResultsBased on a comprehensive analysis of genome-wide association study (GWAS) data from public databases, we mainly used inverse-variance weighted (IVW) to estimate causal relationships, while using MR-Egger, weighted median, simple mode, and weighted mode, and other four methods as supplements. Two-sample MR Analysis revealed no causal relationship between exposure factors (HPV-16 E7 protein and HPV-18 E7 protein) and outcome factors (lung cancer (LUCA) and its subtypes squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD)) in forward MR Analysis using the IVW approach.HPV-16 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 1.002; 95% [CI]: 0.961 − 1.045; p = 0.920; [OR] = 1.023; 95% [CI]: 0.966 − 1.084; p = 0.438; [OR] = 0.994; 95% [CI]: 0.927 − 1.066; p = 0.872); HPV-18 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 0.965; 95% [CI]: 0.914 − 1.019; p = 0.197; [OR] = 0.933; 95% [CI]: 0.834 − 1.043; p = 0.222; [OR] = 1.028; 95% [CI]: 0.945 − 1.118; p = 0.524. It was observed through reverse MR that LUCA and its subtypes LUSC and LUAD were used as exposure factors, and HPV infection (HPV-16 E7 protein and HPV-18 E7 protein) was used as the outcome factors, the results of the IVW method are also invalid.LUCA and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.036; 95% [CI]: 0.761 − 1.411; p = 0.82; [OR] = 1.318; 95% [CI]: 0.949 − 1.830; p = 0.099; LUSC and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.123; 95% [CI]0.847 − 1.489; p = 0.421; [OR] = 0.931; 95% [CI]: 0.660 − 1.313; p = 0.682; LUAD and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.182; 95% [CI] 0.983 − 1.421; p = 0.075; [OR] = 1.017; 95% [CI]: 0.817 − 1.267; p = 0.877.Our results indicate that there is no causal relationship between genetically predicted HPV infection and LUCA and its subtypes LUSC and LUAD. In addition, in the reverse MR analysis, we did not observe a significant causal relationship between LUCA and its subtypes LUSC and LUAD on HPV infection.ConclusionsOur findings do not support a genetic association between HPV infection and lung cancer.

On the informative value of community-based indoor radon values in relation to lung cancer.

Radon is a radioactive gas and a major risk factor for lung cancer (LC). We investigated the dose-response relationship between radon and LC risk in the International Lung Cancer Consortium with 8927 cases and 5562 controls from Europe, North America, and Israel, conducted between 1992 and 2016. Spatial indoor radon exposure in the residential area (sIR) obtained from national surveys was linked to the participants' residential geolocation. Parametric linear and spline functions were fitted within a logistic regression framework. We observed a non-linear spatial-dose response relationship for sIR < 200 Bq/m3. The lowest risk was observed for areas of mean exposure of 58 Bq/m3 (95% CI: 56.1-59.2 Bq/m3). The relative risk of lung cancer increased to the same degree in areas averaging 25 Bq/m3 (OR = 1.31, 95% CI: 1.01-1.59) as in areas with a mean of 100 Bq/m3 (OR = 1.34, 95% CI: 1.20-1.45). The strongest association was observed for small cell lung cancer and the weakest for squamous cell carcinoma. A stronger association was also observed in men, but only at higher exposure levels. The non-linear association is primarily observed among the younger population (age < 69 years), but not in the older population, which can potentially represent different biological radiation responses. The sIR is useful as proxy of individual radon exposure in epidemiological studies on lung cancer. The usual assumption of a linear, no-threshold dose-response relationship, as can be made for individual radon exposures, may not be optimal for sIR values of less than 200 Bq/m3.

The associations between dysregulation of human blood metabolites and lung cancer risk: evidence from genetic data

BackgroundMetabolic dysregulation is recognized as a significant hallmark of cancer progression. Although numerous studies have linked specific metabolic pathways to cancer incidence, the causal relationship between blood metabolites and lung cancer risk remains unclear.MethodsGenomic data from 29,266 lung cancer patients and 56,450 control individuals from the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium (TRICL-ILCCO) were utilized, and findings were replicated using additional data from the FinnGen consortium. The analysis focused on the associations between 486 blood metabolites and the susceptibility to overall lung cancer and its three major clinical subtypes. Various Mendelian randomization methods, including inverse-variance weighting, weighted median estimation, and MR-Egger regression, were employed to ensure the robustness of our findings.ResultsA total of 19 blood metabolites were identified with significant associations with lung cancer risk. Specifically, oleate (OR per SD = 2.56, 95% CI: 1.51 to 4.36), 1-arachidonoylglyceropholine (OR = 1.79, 95% CI: 1.22 to 2.65), and arachidonate (OR = 1.67, 95% CI: 1.16 to 2.40) were associated with a higher risk of lung cancer. Conversely, 1-linoleoylglycerophosphoethanolamine (OR = 0.57, 95% CI: 0.40 to 0.82), ADpSGEGDFXAEGGGVR, a fibrinogen cleavage peptide (OR = 0.60, 95% CI: 0.47 to 0.77), and isovalerylcarnitine (OR = 0.62, 95% CI: 0.49 to 0.78) were associated with a lower risk of lung cancer. Notably, isoleucine (OR = 9.64, 95% CI: 2.55 to 36.38) was associated with a significantly higher risk of lung squamous cell cancer, while acetyl phosphate (OR = 0.11, 95% CI: 0.01 to 0.89) was associated with a significantly lower risk of small cell lung cancer.ConclusionThis study reveals the complex relationships between specific blood metabolites and lung cancer risk, highlighting their potential as biomarkers for lung cancer prevention, screening, and treatment. The findings not only deepen our understanding of the metabolic mechanisms of lung cancer but also provide new insights for future treatment strategies.

Investigating causal associations between pneumonia and lung cancer using a bidirectional mendelian randomization framework

BackgroundPneumonia and lung cancer are both major respiratory diseases, and observational studies have explored the association between their susceptibility. However, due to the presence of potential confounders and reverse causality, the comprehensive causal relationships between pneumonia and lung cancer require further exploration.MethodsGenome-wide association study (GWAS) summary-level data were obtained from the hitherto latest FinnGen database, COVID-19 Host Genetics Initiative resource, and International Lung Cancer Consortium. We implemented a bidirectional Mendelian randomization (MR) framework to evaluate the causal relationships between several specific types of pneumonia and lung cancer. The causal estimates were mainly calculated by inverse-variance weighted (IVW) approach. Additionally, sensitivity analyses were also conducted to validate the robustness of the causalty.ResultsIn the MR analyses, overall pneumonia demonstrated a suggestive but modest association with overall lung cancer risk (Odds ratio [OR]: 1.21, 95% confidence interval [CI]: 1.01 − 1.44, P = 0.037). The correlations between specific pneumonia types and overall lung cancer were not as significant, including bacterial pneumonia (OR: 1.07, 95% CI: 0.91 − 1.26, P = 0.386), viral pneumonia (OR: 1.00, 95% CI: 0.95 − 1.06, P = 0.891), asthma-related pneumonia (OR: 1.18, 95% CI: 0.92 − 1.52, P = 0.181), and COVID-19 (OR: 1.01, 95% CI: 0.78 − 1.30, P = 0.952). Reversely, with lung cancer as the exposure, we observed that overall lung cancer had statistically crucial associations with bacterial pneumonia (OR: 1.08, 95% CI: 1.03 − 1.13, P = 0.001) and viral pneumonia (OR: 1.09, 95% CI: 1.01 − 1.19, P = 0.037). Sensitivity analysis also confirmed the robustness of these findings.ConclusionThis study has presented a systematic investigation into the causal relationships between pneumonia and lung cancer subtypes. Further prospective study is warranted to verify these findings.

Immune cells mediated the causal relationship between the gut microbiota and lung cancer: a Mendelian randomization study.

The gut microbiota (GM) influences the occurrence and progression of lung cancer (LC), with potential involvement of immune cells (IC). We aimed to investigate the causal impact of GM on LC and identify potential immune cell mediators. The utilized data for the Genome-Wide Association Studies (GWAS) were summarized as follows: gut microbiota data from the Dutch Microbiome Project (DMP) (N = 7,738), lung cancer data from the Transdisciplinary Research in Cancer of the Lung (TRICL) and International Lung Cancer Consortium (ILCCO) (Ncase = 29,266, Ncontrol = 56,450) included four types of cancer: NSCLC, LUAD, LUSC, and SCLC, and immune cell data from European populations (N = 3,757). We employed bi-directional two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and mediation analysis to assess the causal relationship between GM and LC and potential immune cell mediators. Bi-directional UVMR analysis revealed that 24 gut microbiota species can affect LC, while LC can affect the abundance of 17 gut microbiota species. Mediation analysis demonstrated that six immune cells mediated the causal relationships of seven gut microbiota species on LC: "CCR7 on naive CD8+ T cell" mediated the causal relationship between s_Alistipes_putredinis and LUAD, with a mediation proportion of 9.5% and P = 0.018; "IgD- CD27- B cell %lymphocyte" mediated the causal relationships between g_Gordonibacter and s_Gordonibacter_pamelaeae with LUSC, with mediation proportions of 11.8% and 11.9%, respectively and P = 0.029; "CD20- CD38- B cell %lymphocyte" mediated the causal relationship between s_Bacteroides_clarus and SCLC, with a mediation proportion of 13.8% and P = 0.005; "CD20 on IgD+ CD38- unswitched memory B cell" mediated the causal relationship between s_Streptococcus_thermophilus and SCLC, with a mediation proportion of 14.1% and P = 0.023; "HLA DR on CD14- CD16+ monocyte" mediated the causal relationship between s_Bifidobacterium_bifidum and SCLC, with a mediation proportion of 8.7% and P = 0.012; "CD45 on Granulocytic Myeloid-Derived Suppressor Cells" mediated the causal relationship between f_Lactobacillaceae and SCLC, with a mediation proportion of 4.0% and P = 0.021. This Mendelian randomization study identified several specific gut microbiotas that exhibit causal relationships with lung cancer and potentially mediate immune cells.

Abstract 7002: RNA m6A modification and lung cancer risk: An epitranscriptome-wide association study

Abstract N6-Methyladenosine (m6A), the most prevalent epitranscriptomic modification in eukaryotic mRNA, determines the fate of target RNAs. Key m6A regulators have been elucidated to be essential for lung cancer cell proliferation. However, the relationship between individual m6A markers and lung cancer risk remains inadequately explored. We conducted an epitranscriptome-wide association study (EpiTWAS) to investigate genetically predicted m6A in association with lung cancer risk. Genetic and m6A data of 30 lung, 12 heart, 28 muscle, and 50 brain tissues from 87 donors predominantly of European ancestry were obtained from Genotype-Tissue Expression (GTEx). For each m6A marker, we built a single-tissue model via elastic net, focusing on lung tissue, and a cross-tissue model through the unified test for molecular signatures (UTMOST) approach, capturing genetic influences on m6A shared by lung and other tissues. SPrediXcan was used to apply these models to data of genome-wide association studies (GWAS) among 38,422 lung cancer cases and 677,930 controls of European descent from International Lung Cancer Consortium (ILCCO), UK Biobank, and FinnGen. For m6A markers significantly associated with lung cancer risk at false discovery rate (FDR)&amp;lt;0.05, we assessed the differential expression of proteins encoded by their target mRNAs in lung cancer versus adjacent normal tissues (200 pairs), using data from Clinical Proteomic Tumor Analysis Consortium (CPTAC). Of the 38,841 high-quality m6A markers in 11,715 genes analyzed, prediction models were built for 6,809 m6A markers in 4,548 genes with performance of R&amp;gt;0.1 (P&amp;lt;0.05), ~85.2% (5,801) of which were single-tissue models. Among these, 28 m6A markers in 26 genes were significantly associated with overall lung cancer risk (FDR&amp;lt;0.05). Notably, 12 (~43%) of these markers in 12 loci are &amp;gt;2 megabases away from any of GWAS-identified lung cancer risk variants. When conditioning on nearby GWAS signals, these 12 associations did not change materially, whereas 15 of the remaining 16 associations lost statistical significance. Analyses by lung cancer histology and smoking status revealed no significant heterogeneity among the 28 associations but identified eight additional m6A markers significantly (FDR&amp;lt;0.05) associated with the risk of adenocarcinoma (n=2), squamous cell carcinoma (n=3), and overall lung cancer among ever- (n=2) or never-smokers (n=1). Of the 33 target RNAs of those 36 m6A markers, 30 encode proteins and 22 of these proteins displayed a significant tumor-normal differential expression at fold change &amp;gt;1.5 and FDR&amp;lt;0.05 in CPTAC lung tissue data. Our study demonstrates the ability of EpiTWAS to decipher GWAS loci and uncover signals potentially missed by GWAS. Our results imply that certain m6A markers may impact lung cancer risk by modulating mRNA translation, underscoring the need for further research to fully unravel the role of m6A in lung cancer etiology. Citation Format: Yaohua Yang, Yaxin Chen, Yawen Qi, Hongmo Liu, Guochong Jia, Jie Ping, Xiao-Ou Shu, Wei Zheng, Weimin Li, Jirong Long, Qiuyin Cai. RNA m6A modification and lung cancer risk: An epitranscriptome-wide association study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7002.

Estimating the health impact of nicotine exposure by dissecting the effects of nicotine versus non-nicotine constituents of tobacco smoke: A multivariable Mendelian randomisation study.

The detrimental health effects of smoking are well-known, but the impact of regular nicotine use without exposure to the other constituents of tobacco is less clear. Given the increasing daily use of alternative nicotine delivery systems, such as e-cigarettes, it is increasingly important to understand and separate the effects of nicotine use from the impact of tobacco smoke exposure. Using a multivariable Mendelian randomisation framework, we explored the direct effects of nicotine compared with the non-nicotine constituents of tobacco smoke on health outcomes (lung cancer, chronic obstructive pulmonary disease [COPD], forced expiratory volume in one second [FEV-1], forced vital capacity [FVC], coronary heart disease [CHD], and heart rate [HR]). We used Genome-Wide Association Study (GWAS) summary statistics from Buchwald and colleagues, the GWAS and Sequencing Consortium of Alcohol and Nicotine, the International Lung Cancer Consortium, and UK Biobank. Increased nicotine metabolism increased the risk of COPD, lung cancer, and lung function in the univariable analysis. However, when accounting for smoking heaviness in the multivariable analysis, we found that increased nicotine metabolite ratio (indicative of decreased nicotine exposure per cigarette smoked) decreases heart rate (b = -0.30, 95% CI -0.50 to -0.10) and lung function (b = -33.33, 95% CI -41.76 to -24.90). There was no clear evidence of an effect on the remaining outcomes. The results suggest that these smoking-related outcomes are not due to nicotine exposure but are caused by the other components of tobacco smoke; however, there are multiple potential sources of bias, and the results should be triangulated using evidence from a range of methodologies.

Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification.

Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12-3.50, P-value = 4.13 × 10-15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99-2.49, P-value = 5.70 × 10-46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72-0.74). Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS.

INTEGRAL‐ILCCO cohort data analysis revealed the association of clonal haematopoiesis with an increased risk of lung cancer

AbstractTo investigate the association between clonal haematopoiesis (CH) and lung cancer risk, we identified CH mutations in 1 059 lung cancer cases and 899 controls using the blood whole‐exome sequencing data generated from the Integrative Analysis of Lung Cancer Etiology and Risk project of the International Lung Cancer Consortium (INTEGRAL‐ILCCO). Based on the variant allele frequency (VAF) of these mutations, we stratified CH carriers into two groups, low VAF (1%–10%) and high VAF (≥10%), respectively. We observed a significant association between the presence of CH mutations and the risk of lung cancer after adjusting for known risk factors (odd ratio, OR = 1.37, 95% confidence interval, CI = 1.02–1.85). Such an association was largely driven by CH mutations with high‐VAF, the OR for high‐VAF CH and low‐VAF CH were 2.54 (1.38–4.93) and 1.14 (0.82–1.6), respectively. Trend analysis indicated a significant dose–response relationship (P trend = 0.004). This association between high‐VAF CH and lung cancer risk remained consistent when subjects were stratified by risk factors or lung cancer histological subtypes. A combination of results from INTEGRAL‐ILCCO, UKBB, and MGBB cohorts resulted in a meta‐analysed OR of 1.36 (95% CI = 1.14–1.62) for all CH carriers and of 1.76 (95% CI = 1.34–2.31) for high‐VAF CH carriers, respectively. In conclusion, our analysis revealed a significant association between CH and increased risk of lung cancer as supported by three independent cohorts.

Association between obstructive sleep apnea and risk of lung cancer: findings from a collection of cohort studies and Mendelian randomization analysis.

Previous cohort studies conducted on large populations have suggested a potential association between obstructive sleep apnea (OSA) and an elevated risk of developing lung cancer. However, limited research has comprehensively investigated the correlation between the two conditions, and the causal effect remains unknown. A comprehensive and systematic search was conducted across various databases, including PubMed, Web of Science, Cochrane Library, and Embase, from their inception dates to November 1, 2023. To assess the relationship between OSA and lung cancer, a meta-analysis was performed. Additionally, a two-sample Mendelian randomization (MR) study was conducted using summary data. The datasets included 336,659 individuals from the FinnGen study for OSA and 27,209 individuals from the International Lung Cancer Consortium study, as well as 420,473 individuals from the UK Biobank study for lung cancer. The estimates from each study were aggregated using the inverse variance-weighted method. Data from six population-based cohort studies, encompassing 6,589,725 individuals, indicated a significant increase in the risk of developing lung cancer among patients with OSA (HR 1.28, 95% CI 1.07-1.54). However, the MR analysis did not support a causal relationship between OSA and lung cancer (OR 1.001, 95% CI 0.929-1.100). This lack of association was consistent across specific subtypes of lung cancer, including non-small-cell lung cancer (OR 1.000, 95% CI 0.999-1.000, p = 0.974), lung adenocarcinoma (OR 0.996, 95% CI 0.906-1.094, p = 0.927), and squamous cell lung carcinoma (OR 1.034, 95% CI 0.937-1.140, p = 0.507). Our meta-analysis findings suggest an elevated risk of lung cancer among individuals with OSA. However, the MR analysis did not provide evidence supporting a causal relationship between OSA and lung cancer. Further investigation is required to uncover the underlying factors contributing to the observed association between OSA and lung cancer risk.

Causal effect of beta-blockers on the risk of lung cancer: a Mendelian randomization study.

It remains uncertain whether there is a causal association of the use of beta-blockers (BBs) on lung cancer risk. We used a two-sample Mendelian randomization (MR) approach to identify the causal association of BBs and lung cancer risk. Twenty-two BB-related single-nucleotide polymorphisms (SNPs) were obtained from the UK Biobank as the instrumental variables (IVs). Genetic summary data information of lung cancer was extracted from the International Lung Cancer Consortium, with a total of 11,348 cases and 15,861 controls. We adopted the inverse-variance weighted (IVW) approach to conduct the MR analyses. Egger-intercept analysis was further performed as sensitivity analysis for pleiotropy evaluation. Additionally, we investigated whether BBs could causally affect the risk of lung cancer through their pharmacological effects. The current IVW analysis suggested a decreased lung cancer risk in BB users [odds ratio (OR) =0.83; 95% confidence interval (CI): 0.73-0.95; P<0.01]. Results of Egger-intercept analysis demonstrated that no pleiotropy was found (P=0.94), which suggested the robustness of the causality. However, there was little evidence that pharmacological effects mediate the association between BBs and lung cancer. The current analysis suggested that BBs could decrease the risk of lung cancer but may be not via its pharmacological effects. Further research is in need for elucidating the underlying mechanisms.

Hypothyroidism reduces the risk of lung cancer through oxidative stress response and the PI3K/Akt signaling pathway: An RNA-seq and Mendelian randomization study

Hypothyroidism has been suggested to play a role in tumor progression. However, the causal association between hypothyroidism and lung cancer remains unknow. To elucidate the potential association between hypothyroidism and lung cancer risk, we employ a Mendelian randomization (MR) approach. MR was performed to analyze pooled data from the International Lung Cancer Consortium (11,348 cases and 15,861 controls; European ancestry) to determine the causal relationship between hypothyroidism and lung cancer. We used 36, 83, and 14 single nucleotide polymorphisms as instrumental variables for hypothyroidism/myxoedema, hypothyroidism, and exercise, respectively. We further investigated the mechanisms involved in transcriptome analysis using data from The Cancer Genome Atlas and Genotype-Tissue Expression database. We conducted an initial validation of intermediary factor using a two-step MR analysis. Genetically predicted hypothyroidism was significantly related to the risk of overall lung cancer, specifically the risk of lung squamous cell cancer (LSCC) but not with the risk of lung adenocarcinoma (LUAD) as assessed using the inverse-variance weighted (IVM) method. A similar causal association was found between hypothyroidism/myxoedema and the risk of lung cancer, LSCC, and LUAD. Transcriptome analysis showed that genes associated with hypothyroidism, lung cancer, and LSCC were enriched in the PI3K/Akt signaling pathway and oxidative stress response. However, genes related to hypothyroidism and LUAD did not exhibit enrichment in these pathways. Hypothyroidism was significantly associated with strenuous sports or other exercises. Moreover, genetically predicted exercise was significantly related to the risk of overall lung cancer, and LSCC, but not LUAD. We detected no horizontal pleiotropy using the MR-PRESSO and MR Egger regression intercept. Hypothyroidism was causally associated with a lower risk of lung cancer, and these effects might be mediated by the oxidative stress response and the PI3K/Akt signaling pathway. Therefore, our study suggests that the potential factors and viable etiologies of hypothyroidism that contributed to lung cancer risk deserve further investigation.

Association of plasma branched-chain amino acid with multiple cancers: A mendelian randomization analysis

Studies have suggested a possible relevance between branched-chain amino acid (BCAA) catabolic enzymes and cancers. However, few studies have explored the variation in circulating concentrations of BCAAs. Our study used bi-directional, two-sample Mendelian randomization (MR) analysis for predicting the causality between the BCAA levels and 9 types of cancers. The largest genome-wide association studies (GWAS) provided data for total BCAAs, valine, leucine, and isoleucine from the UK Biobank. Data on multiple cancer endpoints were collected from various sources, such as the International Lung Cancer Consortium (ILCCO), the Pancreatic Cancer Cohort Consortium 1 (PanScan1), the Breast Cancer Association Consortium (BCAC), the FinnGen Biobank, and the Ovarian Cancer National Alliance (OCAC). The mainly analysis method was the inverse-variance-weighted (IVW). For assessing horizontal pleiotropy, the researchers performed MR-Egger regression and MR-PRESSO global test. Finally, the Cochran's Q test served for evaluating the heterogeneity. Circulating total BCAAs levels (OR 1.708, 95%CI 1.168, 2.498; p=0.006), valine levels (OR 1.747, 95%CI 1.217, 2.402; p<0.001), leucine levels (OR 1.923, 95%CI 1.279, 2.890; p=0.002) as well as isoleucine levels (OR 1.898, 95%CI 1.164, 3.094; p=0.010) positively correlated with the squamous cell lung cancer risk. Nevertheless, no compelling evidence was found to support a causal link between BCAAs and any other examined cancers. Increased circulating total-BCAAs levels, leucine levels, isoleucine levels and valine levels had higher hazard of squamous cell lung cancer. No such associations were found for BCAAs with other cancers.

Revealing a causal relationship between gut microbiota and lung cancer: a Mendelian randomization study.

The gut microbiota has been found to be associated with the risk of lung cancer. However, its causal relationship with various types of lung cancer remains unclear. We conducted a Mendelian randomization (MR) study using the largest genome-wide association analysis of gut microbiota data to date from the MiBioGen consortium, with pooled statistics for various types of lung cancer from the Transdisciplinary Research in Cancer of the Lung, the International Lung Cancer Consortium, and FinnGen Consortium R7 release data. Inverse variance weighted, weighted model, MR-Egger regression, and weighted median were adapted to assess the causal relationship between gut microbiota and various types of lung cancer. Sensitivity analysis was used to test for the presence of pleiotropy and heterogeneity in instrumental variables. A reverse MR analysis was performed on these bacteria to determine their potential role in causing lung cancer. A reverse MR analysis was performed on these bacteria to determine their potential role in causing lung cancer. Multivariable Mendelian randomization (MVMR) was conducted to assess the direct causal impact of gut microbiota on the risk of various types of lung cancer. Using IVW as the primary analytical method, we identified a total of 40 groups of gut microbiota with potential causal associations with various subtypes of lung cancer, of which 10 were associated with lung cancer, 10 with lung adenocarcinoma, 9 with squamous cell lung cancer, and 11 groups of bacteria associated with small cell lung cancer. After performing FDR correction, we further found that there was still a significant causal relationship between Peptococcaceae and lung adenocarcinoma. Sensitivity analyses demonstrated the robustness of these results, with no heterogeneity or pleiotropy found. Our results confirm a causal relationship between specific gut microbiota and lung cancer, providing new insights into the role of gut microbiota in mediating the development of lung cancer.

Large-scale whole exome sequencing studies identify two genes,CTSL and APOE, associated with lung cancer.

Common genetic variants associated with lung cancer have been well studied in the past decade. However, only 12.3% heritability has been explained by these variants. In this study, we investigate the contribution of rare variants (RVs) (minor allele frequency <0.01) to lung cancer through two large whole exome sequencing case-control studies. We first performed gene-based association tests using a novel Bayes Factor statistic in the International Lung Cancer Consortium, the discovery study (European, 1042 cases vs. 881 controls). The top genes identified are further assessed in the UK Biobank (European, 630 cases vs. 172 864 controls), the replication study. After controlling for the false discovery rate, we found two genes, CTSL and APOE, significantly associated with lung cancer in both studies. Single variant tests in UK Biobank identified 4 RVs (3 missense variants) in CTSL and 2 RVs (1 missense variant) in APOE stongly associated with lung cancer (OR between 2.0 and 139.0). The role of these genetic variants in the regulation of CTSL or APOE expression remains unclear. If such a role is established, this could have important therapeutic implications for lung cancer patients.

The causal relationship between thyroid function, autoimune thyroid dysfunction and lung cancer: a mendelian randomization study

BackgroundThe role of thyroid hormones in cancers has been discussed in observational studies; however, the causal relationship between them remains controversial.MethodsThe SNPs associated with hypothyroidism and hyperthyroidism were selected from a FinnGen biobank of 342,499 (190,879 females and 151,620 males) Finnish adult subjects. Data from the Thyroidomics Consortium on 72,167 individuals were used to assess genetically determined thyroid-stimulating hormone (TSH) and free thyroxine (FT4). Lung cancer, lung adenocarcinoma and squamous cell lung cancer GWAS data from the International Lung Cancer Consortium(ILCCO). Six different Mendelian randomization (MR) Methods, including Inverse variance weighted (IVW), MR-Egger, Simple mode, MR-Pleiotropy Residual Sum and Outlier methods (MR-PRESSO), Weighted mode and Weighted median were used to Two-Sample MR analysis. IVW was used as the primary estimate. Sensitivity analyses were examined via four aspects (Cochran’s Q-test, MR Egger intercept analysis, Funnel plot and Leave-one-out sensitivity test).ResultsThe OR of hypothyroidism on lung cancer was 0.918 (95% CI, 0.859–0.982; p = 0.013) in MR analysis with IVW method. No evidence for effects of hyperthyroidism, TSH and FT4 on lung cancer risk was found via six MR methods. Meanwhile, there was no evidence for effects of lung cancer on hypothyroidism through six MR methods. Lung adenocarcinoma and squamous cell lung carcinoma were further analyzed on the basis of lung cancer. The OR of hypothyroidism on lung adenocarcinoma was 0.893(95% CI, 0.813–0.981; p = 0.019), the OR of hypothyroidism on squamous cell lung cancer was 0.888(95%CI,0.797–0.990, p = 0.032) in MR analysis with IVW method.ConclusionIn summary, hypothyroidism genetically had a protective causal association with lung cancer. Furthermore, hypothyroidism had protective effects both on lung adenocarcinoma and squamous cell lung cancer. Further work is needed to elucidate the potential mechanisms.

Association between duration of smoking abstinence before non-small-cell lung cancer diagnosis and survival: a retrospective, pooled analysis of cohort studies

The association between duration of smoking abstinence before non-small-cell lung cancer (NSCLC) diagnosis and subsequent survival can influence public health messaging delivered in lung-cancer screening. We aimed to assess whether the duration of smoking abstinence before diagnosis of NSCLC is associated with improved survival. In this retrospective, pooled analysis of cohort studies, we used 26 cohorts participating in Clinical Outcomes Studies of the International Lung Cancer Consortium (COS-ILCCO) at 23 hospitals. 16 (62%) were from North America, six (23%) were from Europe, three (12%) were from Asia, and one (4%) was from South America. Patients enrolled were diagnosed between June 1, 1983, and Dec 31, 2019. Eligible patients had smoking data before NSCLC diagnosis, epidemiological data at diagnosis (obtained largely from patient questionnaires), and clinical information (retrieved from medical records). Kaplan-Meier curves and multivariable Cox models (ie, adjusted hazard ratios [aHRs]) were generated with individual, harmonised patient data from the consortium database. We estimated overall survival for all causes, measured in years from diagnosis date until the date of the last follow-up or death due to any cause and NSCLC-specific survival. Of 42 087 patients with NSCLC in the COS-ILCCO database, 21 893 (52·0%) of whom were male and 20 194 (48·0%) of whom were female, we excluded 4474 (10·6%) with missing data. Compared with current smokers (15 036 [40·0%] of 37 613), patients with 1-3 years of smoking abstinence before NSCLC diagnosis (2890 [7·7%]) had an overall survival aHR of 0·92 (95% CI 0·87-0·97), patients with 3-5 years of smoking abstinence (1114 [3·0%]) had an overall survival aHR of 0·90 (0·83-0·97), and patients with more than 5 years of smoking abstinence (10 841 [28·8%]) had an overall survival aHR of 0·90 (0·87-0·93). Improved NSCLC-specific survival was observed in 4301 (44%) of 9727 patients who had quit cigarette smoking and was significant at abstinence durations of more than 5 years (aHR 0·87, 95% CI 0·81-0·93). Results were consistent across age, sex, histology, and disease-stage distributions. In this large, pooled analysis of cohort studies across Asia, Europe, North America, and South America, overall survival was improved in patients with NSCLC whose duration of smoking abstinence before diagnosis was as short as 1 year. These findings suggest that quitting smoking can improve overall survival, even if NSCLC is diagnosed at a later lung-cancer screening visit. These findings also support the implementation of public health smoking cessation strategies at any time. The Alan B Brown Chair, The Posluns Family Fund, The Lusi Wong Fund, and the Princess Margaret Cancer Foundation.

Genetically predicted childhood body mass index and lung cancer susceptibility: A two-sample Mendelian randomization study.

The association between adult body mass index (BMI) and lung cancer (LC) susceptibility have been reported, but the causal relationship with childhood BMI remains largely unclear. To evaluate the causal effect of childhood BMI on LC susceptibility, a two-sample Mendelian randomization (MR) study was performed. The two-sample MR analysis utilized 25 single nucleotide polymorphisms (SNPs) as instrumental variables for childhood BMI. Genetic summary data from the International Lung Cancer Consortium and FinnGen databases were analyzed to estimate the causal effect of these SNPs on LC susceptibility. The IVW method was employed as the primary analysis, supplemented by the Weighted Median, MR-Egger, and MR pleiotropy residual sum and outlier test. Our findings indicated that there was no causal association between childhood BMI and the susceptibility of LC (odds ratio [OR]: 1.03, 95% confidence interval [CI]: 0.90-1.17, p = 0.705), lung adenocarcinoma (OR: 0.99, 95% CI: 0.86-1.13, p = 0.832), lung squamous cell carcinoma (OR: 0.97, 95% CI: 0.84-1.13, p = 0.726), and small cell LC (OR: 1.09, 95% CI: 0.82-1.45, p = 0.554) based on the IVW as well as other methods employed. Furthermore, these findings indicated no causal effect of childhood BMI on the LC susceptibility in both ever smokers and never smokers. This study did not conclude a causal effect between childhood BMI and LC susceptibility. However, given the complex nature of cancer development, further studies are needed to verify these findings.

Causal relationship between gastro-esophageal reflux disease and risk of lung cancer: insights from multivariable Mendelian randomization and mediation analysis.

A recent study has reported that anti-reflux surgery reduced the risk of lung cancer. However, the exact causal association between gastro-esophageal reflux disease (GORD) and lung cancer remains obscure. Therefore, we conducted a multivariable and network Mendelian randomization (MR) study to explore this potential association and mediation effect. Independent single nucleotide polymorphisms (SNPs) strongly associated with GORD were selected as instrumental variables (IVs) from the corresponding genome-wide association studies (GWAS). The summary statistics were obtained from the largest GORD GWAS meta-analysis of 367 441 (78 707 cases) European individuals, and the summary statistics of lung cancer and pathological subtypes came from International Lung Cancer Consortium (ILCCO) and FinnGen databases. Univariable and multivariable MR analyses were performed to investigate and verify the causal relationship between genetically predicted GORD and lung cancer. Network MR analysis was conducted to reveal the mediating role of GORD between smoking initiation and lung cancer. The univariable MR analysis demonstrated that GORD was associated with an increased risk of total lung cancer in both ILCCO [inverse variance weighted (IVW): odds ratio (OR) = 1.37, 95% confidence interval (CI) 1.16-1.62, P = 1.70E-04] and FinnGen database (IVW: OR = 1.25, 95% confidence interval CI 1.03-1.52, P = 2.27E-02). The consistent results were observed after adjusting the potential confounders [smoking traits, body mass index (BMI) and type 2 diabetes] in multivariable MR analyses. In subtype analyses, GORD was associated with lung adenocarcinoma (IVW: OR = 1.27, 95% CI 1.02-1.59, P = 3.48E-02) and lung squamous cell carcinomas (IVW: OR = 1.50, 95% CI 1.22-1.86, P = 1.52E-04). Moreover, GORD mediated 32.43% (95% CI 14.18-49.82%) and 25.00% (95% CI 3.13-50.00%) of the smoking initiation effects on lung cancer risk in the ILCCO and FinnGen databases, respectively. This study provides credible evidence that genetically predicted GORD was significantly associated with an increased risk of total lung cancer, lung adenocarcinoma and lung squamous cell carcinomas. Furthermore, our results suggest GORD is involved in the mechanism of smoking initiation-induced lung cancer.

Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers.

Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.